Metabolomics – the link between genotypes and phenotypes

Metabolites are the end products of cellular regulatory processes, and their levels can be regarded as the ultimate response of biological systems to genetic or environmental changes. In parallel to the terms `transcriptome' and `proteome', the set of metabolites synthesized by a biological system constitute its `metabolome'. Yet, unlike other functional genomics approaches, the unbiased simultaneous identification and quantification of plant metabolomes has been largely neglected. Until recently, most analyses were restricted to profiling selected classes of compounds, or to fingerprinting metabolic changes without sufficient analytical resolution to determine metabolite levels and identities individually. As a prerequisite for metabolomic analysis, careful consideration of the methods employed for tissue extraction, sample preparation, data acquisition, and data mining must be taken. In this review, the differences among metabolite target analysis, metabolite profiling, and metabolic fingerprinting are clarified, and terms are defined. Current approaches are examined, and potential applications are summarized with a special emphasis on data mining and mathematical modelling of metabolism.

[1]  Theodor Bücher,et al.  Gleichgewicht und Ungleichgewicht im System der Glykolyse , 1963 .

[2]  C. Sweeley,et al.  Analysis of trimethylsilyl derivatives of carbohydrates by gas chromatography and mass spectrometry , 1969 .

[3]  Reinhart Heinrich,et al.  A linear steady-state treatment of enzymatic chains. General properties, control and effector strength. , 1974, European journal of biochemistry.

[4]  R. F. Adams Determination of amino acid profiles in biological samples by gas chromatography. , 1974, Journal of chromatography.

[5]  K. Tanaka,et al.  Gas-chromatographic method of analysis for urinary organic acids. I. Retention indices of 155 metabolically important compounds. , 1980, Clinical chemistry.

[6]  K. Tanaka,et al.  Gas-chromatographic method of analysis for urinary organic acids. II. Description of the procedure, and its application to diagnosis of patients with organic acidurias. , 1980, Clinical chemistry.

[7]  H. Heldt,et al.  Measurement of subcellular metabolite levels in leaves by fractionation of freeze-stopped material in nonaqueous media. , 1984, Plant physiology.

[8]  A. Groen,et al.  Control of gluconeogenesis in rat liver cells. Flux control coefficients of the enzymes in the gluconeogenic pathway in the absence and presence of glucagon. , 1986, The Biochemical journal.

[9]  E. Jellum,et al.  Mass spectrometry in diagnosis of metabolic disorders. , 1988, Biomedical & environmental mass spectrometry.

[10]  H. Sauter,et al.  Metabolic profiling of plants: a new diagnostic technique , 1991 .

[11]  A. Cornish-Bowden,et al.  Taking enzyme kinetics out of control; putting control into regulation. , 1993, European journal of biochemistry.

[12]  Steven A. Hill,et al.  Metabolic control analysis of plant metabolism , 1994 .

[13]  A. Cornish-Bowden,et al.  Determination of control coefficients in intact metabolic systems. , 1994, The Biochemical journal.

[14]  J. Hofmeyr,et al.  Metabolic regulation: A control analytic perspective , 1995, Journal of bioenergetics and biomembranes.

[15]  C Giersch Determining elasticities from multiple measurements of flux rates and metabolite concentrations. Application of the multiple modulation method to a reconstituted pathway. , 1995, European journal of biochemistry.

[16]  M. Dieuaide-Noubhani,et al.  Quantification of Compartmented Metabolic Fluxes in Maize Root Tips Using Isotope Distribution from 13C- or 14C-Labeled Glucose (*) , 1995, The Journal of Biological Chemistry.

[17]  B. Kholodenko,et al.  Composite control of cell function: metabolic pathways behaving as single control units , 1995, FEBS letters.

[18]  Capillary gas chromatography combined with ion trap detection for quantitative profiling of polyols in cerebrospinal fluid and plasma. , 1995, Analytical biochemistry.

[19]  J. Hofmeyr,et al.  Strategies for Manipulating Metabolic Fluxes in Biotechnology , 1995 .

[20]  H. Kacser,et al.  The control of flux. , 1995, Biochemical Society transactions.

[21]  P. Christen,et al.  L'extraction en phase supercritique des substances d'origine végétale , 1995 .

[22]  K. Knudsen,et al.  Influence of Extraction Solvent and Temperature on the Quantitative Determination of Oligosaccharides from Plant Materials by High-Performance Liquid Chromatography , 1996 .

[23]  H. H. Nijhuis,et al.  Extraction of secondary metabolites from plant material: a review , 1996 .

[24]  D. Fell Understanding the Control of Metabolism , 1996 .

[25]  J. Frisvad,et al.  Using direct electrospray mass spectrometry in taxonomy and secondary metabolite profiling of crude fungal extracts , 1996 .

[26]  T. Kuhara,et al.  Gas chromatographic‐mass spectrometric metabolic profiling of patients with fatal infantile mitochondrial myopathy with de Toni‐Fanconi‐Debré syndrome , 1996, Acta paediatrica Japonica : Overseas edition.

[27]  S. Krauss,et al.  Regulation and control in complex, dynamic metabolic systems: experimental application of the top-down approaches of metabolic control analysis to fatty acid oxidation and ketogenesis. , 1996, Journal of theoretical biology.

[28]  D B Kell,et al.  Genetic programming:  a novel method for the quantitative analysis of pyrolysis mass spectral data. , 1997, Analytical chemistry.

[29]  J. Villadsen,et al.  Modeling isotopomer distributions in biochemical networks using isotopomer mapping matrices. , 1997, Biotechnology and bioengineering.

[30]  H. Bersini,et al.  Frustrated chaos in biological networks. , 1997, Journal of theoretical biology.

[31]  W. Wiechert,et al.  Bidirectional reaction steps in metabolic networks: I. Modeling and simulation of carbon isotope labeling experiments. , 1997, Biotechnology and bioengineering.

[32]  E. Morgan,et al.  Isolation of plant products by supercritical-fluid extraction , 1997 .

[33]  M. Teige,et al.  Model of a quinary structure between Krebs TCA cycle enzymes: a model for the metabolon. , 1997, Biochemistry.

[34]  W. Wiechert,et al.  Bidirectional reaction steps in metabolic networks: II. Flux estimation and statistical analysis. , 1997, Biotechnology and bioengineering.

[35]  D. Fell,et al.  Metabolic Control Analysis of glycolysis in tuber tissue of potato (Solanum tuberosum): explanation for the low control coefficient of phosphofructokinase over respiratory flux. , 1997, The Biochemical journal.

[36]  R. Aebersold,et al.  Ceramide profiling of complex lipid mixtures by electrospray ionization mass spectrometry. , 1997, Analytical biochemistry.

[37]  J. François,et al.  A rapid and reliable method for metabolite extraction in yeast using boiling buffered ethanol , 1997, Yeast.

[38]  J. Ross,et al.  A Test Case of Correlation Metric Construction of a Reaction Pathway from Measurements , 1997 .

[39]  Douglas B. Kell,et al.  Non-linear optimization of biochemical pathways: applications to metabolic engineering and parameter estimation , 1998, Bioinform..

[40]  T. Ferenci,et al.  Effect of Slow Growth on Metabolism of Escherichia coli, as Revealed by Global Metabolite Pool (“Metabolome”) Analysis , 1998, Journal of bacteriology.

[41]  F Baganz,et al.  Systematic functional analysis of the yeast genome. , 1998, Trends in biotechnology.

[42]  M. Silverman,et al.  Functional studies of the rabbit intestinal Na+/glucose carrier (SGLT1) expressed in COS-7 cells: evaluation of the mutant A166C indicates this region is important for Na+-activation of the carrier. , 1998, The Biochemical journal.

[43]  S. Oliver,et al.  Metabolic control analysis as a tool in the elucidation of the function of novel genes , 1998 .

[44]  M. Stitt,et al.  Combined expression of glucokinase and invertase in potato tubers leads to a dramatic reduction in starch accumulation and a stimulation of glycolysis. , 1998, The Plant journal : for cell and molecular biology.

[45]  T Szyperski,et al.  13C-NMR, MS and metabolic flux balancing in biotechnology research , 1998, Quarterly Reviews of Biophysics.

[46]  J. Streeter,et al.  Simultaneous extraction and derivatization of carbohydrates from green plant tissues for analysis by gas-liquid chromatography. , 1998, Analytical biochemistry.

[47]  J. Wolfender,et al.  Liquid chromatography coupled to mass spectrometry and nuclear magnetic resonance spectroscopy for the screening of plant constituents , 1998 .

[48]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[49]  H. Liebich,et al.  Gas chromatographic profiling and pattern recognition analysis of urinary organic acids from uterine myoma patients and cervical cancer patients. , 1998, Journal of chromatography. B, Biomedical sciences and applications.

[50]  D. Kell,et al.  The deconvolution of pyrolysis mass spectra using genetic programming: application to the identification of some Eubacterium species. , 1998, FEMS microbiology letters.

[51]  F. Beaudry,et al.  Metabolite profiling study of propranolol in rat using LC/MS/MS analysis. , 1999, Biomedical chromatography : BMC.

[52]  M. Adams,et al.  Simultaneous determination by capillary gas chromatography of organic acids, sugars, and sugar alcohols in plant tissue extracts as their trimethylsilyl derivatives. , 1999, Analytical biochemistry.

[53]  P. Schmidt,et al.  Isolation, Purity Analysis and Stability of Hyperforin as a Standard Material from Hypericum perforatum L. , 1999, The Journal of pharmacy and pharmacology.

[54]  Martin Vingron,et al.  Computational aspects of expression data , 1999, Journal of Molecular Medicine.

[55]  S. Schuster STUDIES ON THE STOICHIOMETRIC STRUCTURE OF ENZYMATIC REACTION SYSTEMS , 1999 .

[56]  Stephanopoulos,et al.  Metabolite and isotopomer balancing in the analysis of metabolic cycles: I. Theory. , 1999, Biotechnology and bioengineering.

[57]  M. Hamburger,et al.  Pressurized liquid extraction of medicinal plants. , 1999, Journal of chromatography. A.

[58]  W Wiechert,et al.  Bidirectional reaction steps in metabolic networks: IV. Optimal design of isotopomer labeling experiments. , 1999, Biotechnology and bioengineering.

[59]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[60]  Igor Goryanin,et al.  Mathematical simulation and analysis of cellular metabolism and regulation , 1999, Bioinform..

[61]  A J Sinskey,et al.  Metabolite and isotopomer balancing in the analysis of metabolic cycles: II. Applications. , 1999, Biotechnology and bioengineering.

[62]  Juan Carlos Nuño,et al.  METATOOL: for studying metabolic networks , 1999, Bioinform..

[63]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[64]  D. Fell,et al.  Detection of elementary flux modes in biochemical networks: a promising tool for pathway analysis and metabolic engineering. , 1999, Trends in biotechnology.

[65]  S. Sisenwine,et al.  Rapid drug metabolite profiling using fast liquid chromatography, automated multiple-stage mass spectrometry and receptor-binding. , 1999, Journal of chromatography. A.

[66]  W. Wiechert,et al.  Bidirectional reaction steps in metabolic networks: III. Explicit solution and analysis of isotopomer labeling systems. , 1999, Biotechnology and bioengineering.

[67]  Fractionation of Plant Extracts by Supercritical Fluid Extraction and Direct Introduction in Capillary Gas Chromatography using a Programmable Temperature Vaporizer , 1999 .

[68]  Michael Bittner,et al.  Data analysis and integration: of steps and arrows , 1999, Nature Genetics.

[69]  S. Yamaguchi,et al.  Automated metabolic profiling and interpretation of GC/MS data for organic acidemia screening: a personal computer-based system. , 1999, The Tohoku journal of experimental medicine.

[70]  W. Schwab,et al.  Metabolic profile of linoleic acid in stored apples: Formation of 13(R)-hydroxy-9(Z),11(E)-octadecadienoic acid , 1999, Lipids.

[71]  I. Molnár-Perl,et al.  Simultaneous determination of sugars, sugar alcohols, acids and amino acids in apricots by gas chromatography–mass spectrometry , 1999 .

[72]  S. Stein,et al.  Deconvolution gas chromatography/mass spectrometry of urinary organic acids--potential for pattern recognition and automated identification of metabolic disorders. , 1999, Rapid communications in mass spectrometry : RCM.

[73]  S. Stein An integrated method for spectrum extraction and compound identification from gas chromatography/mass spectrometry data , 1999 .

[74]  R. Trethewey,et al.  Metabolic profiling: a Rosetta Stone for genomics? , 1999, Current opinion in plant biology.

[75]  O. Fiehn,et al.  Metabolite profiling for plant functional genomics , 2000, Nature Biotechnology.

[76]  D. Fell,et al.  The small world of metabolism , 2000, Nature Biotechnology.

[77]  I S Kohane,et al.  Mutual information relevance networks: functional genomic clustering using pairwise entropy measurements. , 1999, Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing.

[78]  C Giersch Mathematical modelling of metabolism. , 2000, Current opinion in plant biology.

[79]  W. Vichnewski,et al.  Sonication and liquid chromatography as a rapid technique for extraction and fractionation of plant material , 2000 .

[80]  The Arabidopsis Genome Initiative Analysis of the genome sequence of the flowering plant Arabidopsis thaliana , 2000, Nature.

[81]  D B Kell,et al.  Detection of the dipicolinic acid biomarker in Bacillus spores using Curie-point pyrolysis mass spectrometry and Fourier transform infrared spectroscopy. , 2000, Analytical chemistry.

[82]  Christoph Giersch,et al.  Mathematical modelling of metabolism. , 2000, Current opinion in plant biology.

[83]  A. Brazma,et al.  Gene expression data analysis. , 2001, FEBS letters.

[84]  B. Palsson,et al.  The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[85]  Gordon Allison,et al.  Transgenic plants as factories for biopharmaceuticals , 2000, Nature Biotechnology.

[86]  Athel Cornish-Bowden,et al.  Technological and Medical Implications of Metabolic Control Analysis , 2000 .

[87]  J. Nielsen,et al.  Metabolic network analysis of Penicillium chrysogenum using (13)C-labeled glucose. , 2000, Biotechnology and bioengineering.

[88]  O. Fiehn,et al.  Identification of uncommon plant metabolites based on calculation of elemental compositions using gas chromatography and quadrupole mass spectrometry. , 2000, Analytical chemistry.

[89]  Robert Eisenthal,et al.  Computer Simulation as A Tool for Studying Metabolism and Drug Design , 2000 .

[90]  Ute Roessner,et al.  Simultaneous analysis of metabolites in potato tuber by gas chromatography-mass spectrometry. , 2000 .

[91]  D. Fell,et al.  A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks , 2000, Nature Biotechnology.

[92]  I. Wilson,et al.  An NMR‐based metabonomic approach to investigate the biochemical consequences of genetic strain differences: application to the C57BL10J and Alpk:ApfCD mouse , 2000, FEBS letters.

[93]  J. Nielsen,et al.  Metabolic network analysis. A powerful tool in metabolic engineering. , 2000, Advances in biochemical engineering/biotechnology.

[94]  R. Neubert,et al.  Profiling of human stratum corneum ceramides by liquid chromatography-electrospray mass spectrometry , 2000 .

[95]  P. Guenot,et al.  Analysis of amines in plant materials. , 2000, Journal of chromatography. B, Biomedical sciences and applications.

[96]  D. Fell,et al.  Modelling photosynthesis and its control. , 2000, Journal of experimental botany.

[97]  Athel Cornish-Bowden,et al.  From genome to cellular phenotype—a role for metabolic flux analysis? , 2000, Nature Biotechnology.

[98]  M. Novotny,et al.  Steroid profiles determined by capillary electrochromatography, laser-induced fluorescence detection and electrospray-mass spectrometry. , 2000, Journal of chromatography. A.

[99]  M. D. Luque de Castro,et al.  Continuous subcritical water extraction of medicinal plant essential oil: comparison with conventional techniques. , 2000, Talanta.

[100]  木村 正彦,et al.  Automated metabolic profiling and interpretation of GC/MS data for organic acidemia screening : a personal computer-based system , 2000 .

[101]  Douglas B. Kell,et al.  Genomic computing: explanatory modelling for functional genomics , 2000, GECCO.

[102]  Albert-László Barabási,et al.  Error and attack tolerance of complex networks , 2000, Nature.

[103]  Susumu Goto,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 2000, Nucleic Acids Res..

[104]  Douglas B. Kell,et al.  Snapshots of Systems , 2000 .

[105]  P M Bramley,et al.  Application of high‐performance liquid chromatography with photodiode array detection to the metabolic profiling of plant isoprenoids , 2000 .

[106]  U. Sauer,et al.  GC‐MS Analysis of Amino Acids Rapidly Provides Rich Information for Isotopomer Balancing , 2000, Biotechnology progress.

[107]  E. Ong,et al.  Pressurized liquid extraction of berberine and aristolochic acids in medicinal plants. , 2000, Journal of chromatography. A.

[108]  M. Reily,et al.  Metabonomics: evaluation of nuclear magnetic resonance (NMR) and pattern recognition technology for rapid in vivo screening of liver and kidney toxicants. , 2000, Toxicological sciences : an official journal of the Society of Toxicology.

[109]  R. Albert,et al.  The large-scale organization of metabolic networks , 2000, Nature.

[110]  J. K. Roberts,et al.  NMR adventures in the metabolic labyrinth within plants. , 2000, Trends in plant science.

[111]  P. Singh,et al.  Safety aspects of genetically modified foods of plant origin Report of a Joint FAO / WHO Expert Consultation on F oods Derived from Biotechnology , 2000 .

[112]  M. Warne,et al.  An NMR-based metabonomic investigation of the toxic effects of 3-trifluoromethyl-aniline on the earthworm Eisenia veneta , 2000, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[113]  U. Roessner,et al.  Analysis of the compartmentation of glycolytic intermediates, nucleotides, sugars, organic acids, amino acids, and sugar alcohols in potato tubers using a nonaqueous fractionation method. , 2001, Plant physiology.

[114]  B. Palsson,et al.  In silico predictions of Escherichia coli metabolic capabilities are consistent with experimental data , 2001, Nature Biotechnology.

[115]  D. Fell,et al.  Computer modelling and experimental evidence for two steady states in the photosynthetic Calvin cycle. , 2001, European journal of biochemistry.

[116]  Metabolic profiling allows comprehensive phenotyping of genetically or environmentally modified plant systems. , 2001, The Plant cell.

[117]  Thomas Linke,et al.  Visualizing plant metabolomic correlation networks using clique-metabolite matrices , 2001, Bioinform..

[118]  D. Kell,et al.  A functional genomics strategy that uses metabolome data to reveal the phenotype of silent mutations , 2001, Nature Biotechnology.

[119]  Rainer Fuchs,et al.  Analysis of temporal gene expression profiles: clustering by simulated annealing and determining the optimal number of clusters , 2001, Bioinform..

[120]  O. Fiehn,et al.  Integrated studies on plant biology using multiparallel techniques. , 2001, Current opinion in biotechnology.

[121]  Isabel Rojas,et al.  A graph layout algorithm for drawing metabolic pathways , 2001, Bioinform..

[122]  Douglas B. Kell,et al.  Explanatory Analysis of the Metabolome Using Genetic Programming of Simple, Interpretable Rules , 2000, Genetic Programming and Evolvable Machines.

[123]  C. Jay-Allemand,et al.  Use of antioxidants in extraction of tannins from walnut plants , 1991, Journal of Chemical Ecology.